The present invention relates to pharmaceutical agents. In particular, the present invention relates to compounds, pharmaceutical formulations, and methods useful for treating inflammation and inflammation-related disorders, such as, for example, arthritis.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used pharmacological agents worldwide. They are commonly prescribed for the relief of pain, stiffness, and joint swelling for patients with osteoarthritis and rheumatoid arthritis, conditions estimated to affect 12.1% and 1.0%, respectively, of adults in the United States (Lawrence R C, Helmick C G, Arnett F C, et al. xe2x80x9cEstimates of the prevalence of arthritis and selected musculoskeletal disorders in the United Statesxe2x80x9d Arthritis Rheum (1998) 41 (5): 778-99).
Although NSAIDs are generally well tolerated, upper gastrointestinal adverse events are frequently associated with their use. Symptoms range from dyspepsia, nausea, and abdominal pain to more serious complications of mucosal ulceration such as bleeding and perforation. Such upper gastrointestinal complications are the most frequent serious complication of NSAID use and are probably contributory to most NSAID-related deaths. Approximately 16,500 NSAID-related deaths are estimated to occur annually in the US (among 13 million patients exposed to the drugs, see Singh G., Triadafilopoulos G., xe2x80x9cEpidemiology of NSAID induced gastrointestinal complicationsxe2x80x9d J. Rheumatol., (1999) 26 Suppl. 56: 18-24).
NSAIDs act by inhibiting the activity of the enzyme cyclo-oxygenase (COX), and thereby prostaglandin and thromboxane production. COX exists as two isoforms, COX-1 and COX-2. The gastrointestinal adverse events associated with long term NSAID use are believed to result from the inhibition of COX-1. Other less frequent adverse events such as bleeding complications, fluid and electrolyte disorders, acute renal failure, and renal papillary necrosis have also been attributed to inhibition of this enzyme. In contrast, the anti-inflammatory and analgesic effects of NSAIDs are thought to result from inhibition of COX-2.
Certain 1, 2, 4- and 1, 3, 4-thiadiazoles bearing tert-butylphenol moieties and other structurally related compounds are known to provide activity as inhibitors of cyclooxygenase and/or 5-lipoxygenase (see, for example, U.S. Pat. No. 5,510,361 to Scherz; Song Y., Conner D. T., Sercel A. D., Sorenson R. J., Doubleday R., J. Med. Chem. Vol. 42 (1999), pp. 1161-1169; Mullican M. D., Wilson M. W., Connor D. T., Kostlan C. R., Schrier D. J., Dyer R. D., J. Med. Chem., Vol. 36 (1993), pp. 1090-1099). However, there are very few known compounds that are able to selectively inhibit COX-2 in the presence of COX-1 (see U.S. Pat. No. 5,616,601 to Khanna, et al.).
Accordingly, there is a need for compounds and pharmaceutical compositions useful for selectively inhibiting COX-2 in the presence of COX-1, thereby minimizing the pathological side effects associated with NSAID use while maximizing the desired anti-inflammatory and analgesic effects provided by NSAIDs.
In accordance with the present invention, there are provided compounds and pharmaceutical compositions useful for the selective inhibition of COX-2 in the presence of COX-1. As a result, invention compounds and compositions provide anti-inflammatory relief to a subject in need thereof while dramatically reducing the occurrence of side effects in the subject. Compounds contemplated for use in the practice of the present invention are substituted heterocyclic compounds containing amidinyl and imidazolyl groups.
In accordance with additional embodiments of the present invention, there are provided methods for treating inflammation related conditions, methods for treating pathological conditions of the skin, methods for reducing side effects associated with anti-inflammatory agents, and methods for selectively inhibiting COX-2 in the presence of COX-1.